The present study has identified several novel variants which might have a profound effect on the clinical presentation of HNSCC. Variants previously reported viz., rs200204830 of TRDMT1, rs757211277, rs566390868, rs769590067 of DNMT3A, rs121908946, rs770751820 of DNMT3B. Protein stability and pathogenicity analysis revealed three variants R729Q, E907K (TRDMT1) and R840Q (DNMT3B) which were highly pathogenic with scores less than 3.0. The gene discussed is DNMT3B; the disease is head and neck squamous cell carcinoma.